LEO says…invert that aromatic ring, eh?

Canadian Sylvain Canesi and co-workers at the Laboratoire de Méthodologie et Synthèse de Produits Naturels in Quebec (wow, that’s a mouthful) have established an interesting way to establish the dihydrofurano[2,3-b]benzofuran core present in a number of interesting natural products via what they call “aromatic umpolung.” Oxidation of a substituted phenol or sulfonyl amine with PhI(OAc)2 leads to an electrophilic, cationic intermediate susceptible to attack by all manner of nucleophiles, including furans. Once the furan has attacked, an intramolecular cyclization takes place that ties together the phenolic O or N-sulfonyl and the furan. There’s a substantial regiochemical issue with this process, as the furan could attack either carbon ortho to the heteroatom. The group solved this problem by selectively substituting the less hindered ortho position with TMS, leading to nice yields of the “1-2-3” benzofuran. Direct oxidation leads to a mixture of the “1-2-3” and the “1-2-4.”This methodology was applied to synthesize desbromopanacene in only six steps in a back-patting overall yield of 13%. Further proof that, as one of my old professors used to say, “aromaticity is not king.”

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3 Comments

  1. Comment #1: I’m starting to see more and more of these methodology-driven small molecule syntheses in the literature, and I really like it. It puts a little utility to methodology that would otherwise be ignored at first glace.

    Comment #2: The TBAF/CsF in hot DMF looks rather harsh, which makes the methodology slightly unappealing (at least in my mind).

    Reply

  2. Very nice article thank you so much to have shared it.
    I knew regular “aliphatic Umpolung” it is really impressive to have expanded it to aromatic. Wow!!Five steps versus 9 or 15.

    Reply

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